MULTIPLE SEVERE OBESITY RISK GENES IN UTAH PEDIGREES

描述(由申请人提供)：犹他州严重肥胖(BMIS35公斤/平方米)家系中的多个严重肥胖风险基因包括肥胖症的一个特殊子集，其疾病、残疾和死亡的风险极高。重度肥胖具有显著的遗传成分，目前的假设表明，与导致轻度或中度肥胖的基因相比，导致重度肥胖的潜在基因具有更大的影响(或更大的外显性)。统计模型的改进导致了更多已发表的关于遗传上位性和性别特异性效应的证据，支持了长期以来的观点，即肥胖是一种复杂的疾病，涉及多个基因，以复杂的方式相互作用。我们在这里提出了一种新的严重肥胖易感基因TBC1D1的证据，该基因明显分离于患有严重肥胖症的女性家庭成员，并解释了&gt；9LOD评分的大部分。一组独特的犹他州大型家系与许多非常严重的肥胖受试者导致了如此戏剧性的关联证据，随后是显著的关联和生物学证据。此外，有证据表明，染色体4Q上的另一个未连锁的基因座显示出与TBC1D1统计上相互作用的强有力证据，因此，通过只分析分离TBC1D1的家系来对TBC1D1进行条件处理，可以将4Q LOD得分从1.7提高到5.0。由于Tbc1d1基因的存在并不会导致所有携带者的严重肥胖，上述结果表明，其他基因(S)也是充分表达肥胖所必需的。我们还发表了证据表明，20号染色体上的一个基因座似乎包含两个紧密相连的基因，一个是显性基因，另一个是隐性基因，对严重肥胖有影响(LOD=4.9)。该基因座被放置在一个同源基因的小鼠品系中，该品系也显示出多种肥胖表型的证据。此外，当检查分离了TBC1D1和4Q基因座的家系的20号染色体LOD得分时，一些家系还有额外的重叠。这进一步表明，这些家系包含多个基因以未知的方式共同作用，导致这些家系中严重肥胖的密集聚集。本申请建议通过精细定位和测序识别区域4Q基因和20号染色体基因(S)，以检测这些基因的非加性和性别特异性效应。由于已经确定了TBC1D1，这项研究的优势是对一个已知的、常见的易感基因进行条件作用，以找到更多的基因，并模拟它们如何导致严重肥胖。这组信息丰富的家谱将被用来进一步揭开严重肥胖症遗传基础的复杂性，这可能有助于理解不那么严重的肥胖症。验证将在波利尼西亚家族的大型病例/对照系列中进行测试，并在20号染色体的同源小鼠模型中进行测试。

DESCRIPTION (provided by applicant): Multiple Severe Obesity Risk Genes in Utah Pedigrees Severe obesity (BMIS35 kg/m2) comprises a special subset of obesity for which the risk of disease, disability, and mortality is extremely high. Severe obesity has a significant genetic component and current hypotheses suggest underlying genes for severe obesity have larger effects (or greater penetrance) than genes contributing to mild or moderate obesity. Improvements in statistical modeling have led to increased published evidence of genetic epistasis and gender-specific effects, supporting the long-held view that obesity is a complex disease involving multiple genes that interact in complex ways. Evidence is presented herein of a new susceptibility gene we have identified for severe obesity, TBC1D1, that clearly segregates in female family members with severe obesity and explains most of the >9 LOD score. The unique set of large Utah pedigrees with many very severely obese subjects led to such dramatic linkage evidence, followed by significant association and biological evidence. Furthermore, evidence is presented that another unlinked locus on chromosome 4q shows strong evidence of statistical interaction with TBC1D1, such that conditioning on TBC1D1 by analyzing only families segregating TBC1D1 increases the 4q LOD score from 1.7 to 5.0. Since the presence of TBC1D1 does not lead to severe obesity in all carriers, the above result suggests that other gene(s) are also necessary for full expression of obesity. We have also published evidence that a locus on chromosome 20 appears to contain two closely linked genes, one with a dominant and one with a recessive effect on severe obesity (LOD=4.9). This locus was placed in a congenic mouse line which also showed evidence for multiple obesity phenotypes. Further, when the chromosome 20 LOD scores from families segregating for TBC1D1 and the 4q locus were examined, there was additional overlap of some pedigrees. This further suggests that these pedigrees contain multiple genes acting together in unknown fashion resulting in the dense aggregation of severe obesity in these pedigrees. This application proposes to identify, through fine mapping and sequencing, the region 4q gene and chromosome 20 gene(s) to examine nonadditive and gender-specific effects of these genes. Because TBC1D1 has already been identified, this study has the advantage of conditioning on a known, common, susceptibility gene in order to find additional genes and model how they might lead to severe obesity. This highly informative set of pedigrees will be used to further unravel the complexity of the genetic underpinnings of severe obesity that may contribute to the understanding of less severe obesity. Validation will be tested in a large case/control series, Polynesian families, and, for chromosome 20, in the congenic mouse model.